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The Spherical Tokamak for Energy Production (STEP) programme is an ambitious but challenging endeavour to design and deliver a prototype fusion power plant. It is a rapid, fast-moving programme, designing a first of a kind device in a Volatile, Uncertain, Complex and Ambiguous (VUCA) environment, and digital tools play a pivotal role in managing and navigating this space. Digital helps manage the complexity and sheer volume of information. Advanced modelling and simulation techniques provide a platform for designers to explore various scenarios and iteratively refine designs, providing insights into the intricate interplay of requirements, constraints and design factors across physics, technology and engineering domains and aiding informed decision-making amidst uncertainties. It also provides a means of building confidence in the new scientific, technological and engineering solutions, given that a full-scale-integrated precursor test is not feasible, almost by definition. The digital strategy for STEP is built around a vision of a digital twin of the whole plant. This will evolve from the current digital shadow formed by system architecting codes and complex workflows and will be underpinned by developing capabilities in plasma, materials and engineering simulation, data management, advanced control, industrial cybersecurity, regulation, digital technologies and related digital disciplines. These capabilities will help address the key challenges of managing the complexity and quantity of information, improving the reliability and robustness of the current digital shadow and developing an understanding of its validity and performance. This article is part of the theme issue 'Delivering Fusion Energy – The Spherical Tokamak for Energy Production (STEP)'. [ABSTRACT FROM AUTHOR]

The measurement of the electronic bandgap and exciton binding energy in quasi-one-dimensional materials such as carbon nanotubes is challenging due to many-body effects and strong electron–electron interactions. Unlike bulk semiconductors, where the electronic bandgap is well known, the optical resonance in low-dimensional semiconductors is dominated by excitons, making their electronic bandgap more difficult to measure. In this work, we measure the electronic bandgap of networks of polymer-wrapped semiconducting single-walled carbon nanotubes (s-SWCNTs) using non-ideal p-n diodes. We show that our s-SWCNT networks have a short minority carrier lifetime due to the presence of interface trap states, making the diodes non-ideal. We use the generation and recombination leakage currents from these non-ideal diodes to measure the electronic bandgap and excitonic levels of different polymer-wrapped s-SWCNTs with varying diameters: arc discharge (~1.55 nm), (7,5) (0.83 nm), and (6,5) (0.76 nm). Our values are consistent with theoretical predictions, providing insight into the fundamental properties of networks of s-SWCNTs. The techniques outlined here demonstrate a robust strategy that can be applied to measuring the electronic bandgaps and exciton binding energies of a broad variety of nanoscale and quantum-confined semiconductors, including the most modern nanoscale transistors that rely on nanowire geometries. [ABSTRACT FROM AUTHOR]

This article explores the pathophysiology of sporadic vestibular schwannomas (VS), which are benign tumors that can cause neurological and otological issues. The study used single cell RNA sequencing, ATAC sequencing, and whole exome sequencing to analyze the tumor microenvironment (TME) of VS. The findings revealed diverse populations of tumor Schwann cells, stromal cells, and immune cells within the TME. The researchers identified two molecular subtypes of sporadic VS, with the "Injury-like" subtype being enriched for myeloid cells and potentially driven by recruitment of these cells via CSF1 signaling. These findings provide insights into potential molecular targets for treating sporadic VS. [Extracted from the article]

Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to VS pathogenesis remains poorly understood. In this study, we perform scRNA-seq on 15 VS, with paired scATAC-seq (n = 6) and exome sequencing (n = 12). We identify diverse Schwann cell (SC), stromal, and immune populations in the VS TME and find that repair-like and MHC-II antigen-presenting SCs are associated with myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors reveals Injury-like tumors are associated with larger tumor size, and scATAC-seq identifies transcription factors associated with nerve repair SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggest that Injury-like VS-SCs recruit myeloid cells via CSF1 signaling. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be therapeutically targeted. Vestibular schwannomas are benign tumours which can lead to neurological symptoms and morbidity. Here, the authors use single cell RNA-seq and ATAC-seq to identify Schwann cell subtypes in the tumour microenvironment which mimic a nerve injury phenotype. [ABSTRACT FROM AUTHOR]

Accessible Summary: What is known on the subject?: International guidelines for trans‐and‐gender‐non‐conforming (TGNC) exists in outpatient settings.Compared to cisgender and heterosexual people, TGNC individuals are at a higher risk of mental health difficulties and have higher rates of inpatient mental health treatment. What does this paper add to existing knowledge?: An international scoping review identifying the lack of guidelines existing for TGNC individuals in inpatient mental health settings. Compared to psychiatrists and psychologists, mental health nursing has the most contact with patients admitted for inpatient psychiatric treatment. The study identifies unaddressed needs in gender affirming policies and outlines preliminary policy recommendations to assist mental health staff in improving TGNC patient quality of care within the United States. What are the implications for practice?: Reforming existing guidelines or creating new guidelines based on the identified themes and gaps to improve the well‐being and treatment outcomes of TGNC individuals in inpatient psychiatric settings within the United States. Introduction: Access to culturally sensitive care is critical for addressing known mental health disparities among trans‐and gender‐non‐conforming (TGNC) individuals. Although there has been a proliferation of TGNC healthcare guidelines from accrediting bodies, policies have failed to address the needs of TGNC patients in inpatient psychiatric settings. Aim: To identify unaddressed needs in policies and policy recommendations for the care of TGNC patients to inform recommendations for change. Method: A scoping review protocol was developed following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses 850 articles were reduced to seven relevant articles with six themes identified via thematic analysis. Results: Six themes were identified: lack of consistency in preferred and pronoun use, lack of communication among providers, lack of training in TGNC healthcare, personal bias, lack of formal policies, and housing segregation by sex rather than gender. Discussion: The creation of new guidelines or bolstering of existing guidelines to specifically address identified themes and gaps may improve the well‐being and treatment outcomes of TGNC individuals in inpatient psychiatric settings. Implications for practice: To provide a foundation for future studies to integrate these identified gaps and inform the future development of comprehensive formal policies that generalize TGNC care in inpatient settings. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to gather validity evidence according to Messick's framework for a novel 3D‐printed simulator for myringotomy with ventilation tube insertion for use in technical skills training of otorhinolaryngology (ORL) residents. Methods: The study included 15 junior ORL residents (trainees) and 13 experienced teaching otolaryngologists (experts). Experts and trainees first received an identically structured introduction to the procedure, simulator, and simulation setup. Five procedures performed by each participant were video‐recorded and ordered randomly for blinded rating by two independent raters. The rating tools used were a global rating scale (GBRS) and a task‐specific checklist. Validity evidence was collected according to Messick's framework. Differences in time consumption and performance scores were analyzed. Finally, a pass/fail standard was established using the contrasting groups' method. Results: Trainees used significantly more time per procedure (109 s, 95% CI: 99–120) than experts (82 s, 95% CI: 71–93; p <.001). Adjusted for repetition and rater leniency, experts achieved an average GBRS score of 18.8 (95% CI: 18.3–19.2) out of 20 points, whereas trainees achieved an average of 17.1 points (95% CI: 16.6–17.5; p <.001). In contrast to the task‐specific checklist, the GBRS score discriminated between repetition number and participant experience. The pass/fail standard for the GBRS was established at 18.4 points. Conclusion: We established educational validity evidence for a novel 3D‐printed model for simulation‐based training of ventilation tube insertion and established a reliable pass/fail standard. Level of Evidence: 1b. [ABSTRACT FROM AUTHOR]

Each tumour contains diverse cellular states that underlie intratumour heterogeneity (ITH), a central challenge of cancer therapeutics1. Dozens of recent studies have begun to describe ITH by single-cell RNA sequencing, but each study typically profiled only a small number of tumours and provided a narrow view of transcriptional ITH2. Here we curate, annotate and integrate the data from 77 different studies to reveal the patterns of transcriptional ITH across 1,163 tumour samples covering 24 tumour types. Among the malignant cells, we identify 41 consensus meta-programs, each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many tumours. The meta-programs cover diverse cellular processes including both generic (for example, cell cycle and stress) and lineage-specific patterns that we map into 11 hallmarks of transcriptional ITH. Most meta-programs of carcinoma cells are similar to those identified in non-malignant epithelial cells, suggesting that a large fraction of malignant ITH programs are variable even before oncogenesis, reflecting the biology of their cell of origin. We further extended the meta-program analysis to six common non-malignant cell types and utilize these to map cell–cell interactions within the tumour microenvironment. In summary, we have assembled a comprehensive pan-cancer single-cell RNA-sequencing dataset, which is available through the Curated Cancer Cell Atlas website, and leveraged this dataset to carry out a systematic characterization of transcriptional ITH.A study identifies 41 consensus gene expression meta-programs that are coordinately upregulated in subpopulations of malignant cells across tumour types, providing a comprehensive picture of hallmarks of intratumour heterogeneity. [ABSTRACT FROM AUTHOR]

Mandibular fractures are among the most common facial fractures resulting from trauma. The nature of the injury, involved facial structures, presence of associated injuries, the dental status of the patient, comorbid conditions, and psychosocial context all must be considered by the surgeon when planning the optimal treatment for these patients. While consensus exists for many aspects of the management of mandibular trauma, some elements remain controversial. Three such topics—antibiotic therapy, treatment of subcondylar fractures, and management of the third molar—remain particularly controversial, with significant heterogeneity in practice patterns and without widely accepted evidence-based guidelines to standardize care. The goals of this work are to (1) review the historical perspective underlying these controversies, (2) summarize recent evidence shaping the current debate, and (3) highlight opportunities for continued efforts to identify best practices. [ABSTRACT FROM AUTHOR]

Wilhelm (Forthcom Synth 199:6357–6369, 2021) has recently defended a criterion for comparing structure of mathematical objects, which he calls Subgroup. He argues that Subgroup is better than SYM ∗ , another widely adopted criterion. We argue that this is mistaken; Subgroup is strictly worse than SYM ∗ . We then formulate a new criterion that improves on both SYM ∗ and Subgroup, answering Wilhelm’s criticisms of SYM ∗ along the way. We conclude by arguing that no criterion that looks only to the automorphisms of mathematical objects to compare their structure can be fully satisfactory. [ABSTRACT FROM AUTHOR]

In his book Philosophy of Logic, Putnam (1971) presents a short argument which reads like—and indeed, can be reconstructed as—a formal proof that a nominalistic physics is impossible. The aim of this paper is to examine Putnam's proof and show that it is not compelling. The precise way in which the proof fails yields insight into the relation that a nominalistic physics should bear to standard physics and into Putnam's indispensability argument. [ABSTRACT FROM AUTHOR]

Purpose: Glioblastoma (GBM) is the most common and deadliest brain tumor with unrelenting and rapid disease progression. The standard of care for GBM is surgical excision followed by radiation with concurrent and adjuvant temozolomide-centered chemotherapy (TMZ). Treatment failure and resistance is the rule and despite advances in imaging technology, early detection of treatment failure or impending resistance remains a challenge. There is a dire, unmet, need in clinical practice for minimally-invasive diagnostic tools to enable timely understanding of disease progression and treatment response. Here, we aim to address this clinical need by leveraging a unique characteristic of GBM: the overexpression of the α2 variant of the IL-13 receptor in over 75% of GBM tumors. Methods: In this study we examined patients with primary GBM from Penn State and Cleveland Clinic compared to healthy controls. Results: IL13Rα2 was detectable in plasma of GBM patients using ELISA but detection could be optimized by PEG precipitation to enrich for extracellular vesicles (EVs). Patients with GBM had elevated levels of plasma IL13Rα2, which correlated to levels of this receptor in the tumor tissue. Elevated plasma levels of IL13Rα2 predicted longer overall survival (OS) (19.8 vs. 13.2 months). Similarly, detection of IL13Rα2 + cells in tumor tissue also predicted longer OS (22.1 vs. 12.2 months). Conclusion: These findings strongly suggest that expression of the IL13Rα2 receptor confer survival advantage in GBM patients, which can be determined through a minimally-invasive liquid biopsy. Detection of plasma IL13Rα2 can also be used to select GBM patients for targeted tumor therapy. [ABSTRACT FROM AUTHOR]

This is an essay review of Jill North's book Physics, Structure, and Reality. It focuses on two of the main topics of the book. The first is North's idea that we can use coordinates as a window into the structure that a theory posits; the second is North's argument for the inequivalence of Lagrangian and Newtonian mechanics. [ABSTRACT FROM AUTHOR]

This paper presents a simple pair of first-order theories that are not definitionally (nor Morita) equivalent, yet are mutually conservatively translatable and mutually ‘surjectively’ translatable. We use these results to clarify the overall geography of standards of equivalence and to show that the structural commitments that theories make behave in a more subtle manner than has been recognized. [ABSTRACT FROM AUTHOR]

In his 1935 Gedankenexperiment, Erwin Schrödinger imagined a box with a cat and a poisonous substance which has a 50% probability of being released, based on the decay of a radioactive atom. As such, the life of the cat and the state of the poison become entangled, and the fate of the cat is determined upon opening the box. We present an experimental technique that keeps the cat alive on any account. This method relies on the time-resolved Hongâ€"Ouâ€"Mandel effect: two long, identical photons impinging on a beam splitter always bunch in either of the outputs. Interpreting the first photon detection as the state of the poison, the second photon is identified as the state of the cat. Even after the collapse of the first photon’s state, we show their fates are intertwined through quantum interference. We demonstrate this by a sudden phase change between the inputs, administered conditionally on the outcome of the first detection, which steers the second photon to a pre-defined output and ensures that the cat is always observed alive. [ABSTRACT FROM AUTHOR]

As we enter a chronic phase of the SARS-CoV-2 pandemic, with uncontrolled infection rates in many places, relative regional susceptibilities are a critical unknown for policy planning. Tests for SARS-CoV-2 infection or antibodies are indicative but unreliable measures of exposure. Here instead, for four highly-affected countries, we determine population susceptibilities by directly comparing country-wide observed epidemic dynamics data with that of their main metropolitan regions. We find significant susceptibility reductions in the metropolitan regions as a result of earlier seeding, with a relatively longer phase of exponential growth before the introduction of public health interventions. During the post-growth phase, the lower susceptibility of these regions contributed to the decline in cases, independent of intervention effects. Forward projections indicate that non-metropolitan regions will be more affected during recurrent epidemic waves compared with the initially heavier-hit metropolitan regions. Our findings have consequences for disease forecasts and resource utilisation. [ABSTRACT FROM AUTHOR]

Background: For human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), management recommendations for patients with a single metastatic lymph node <6 cm in diameter remain nebulous, leading to treatment heterogeneity in this common subgroup of patients. Methods: We utilized the National Cancer Database to perform survival and multivariable analyses of patients with HPV+ OPSCC with one positive lymph node <6 cm and negative surgical margins. Results: We found that 5‐year survival is comparable between patients who receive surgery and adjuvant radiation versus surgery alone. In multivariable analyses, we found no significant difference in the hazard ratio of overall survival after adjusting for various potential confounders. Conclusions: These data suggest that patients with margin‐negative HPV+ OPSCC with a single positive lymph node <6 cm have comparable survival with or without adjuvant radiation. Future studies exploring outcomes for this specific group in randomized‐controlled trials will be critical for further evaluating these initial observations. [ABSTRACT FROM AUTHOR]

The article presents a mixed-methods assessment of an educational intervention proposed by a partnership between Pulaski County Special School District, the University of Arkansas at Little Rock, Philander Smith College, and plaintiffs in a longstanding federal desegregation lawsuit. The Donaldson Scholars Saturday Academy is part of a plan, approved by the Federal Court's Eastern District of Arkansas in 2014, designed to improve educational achievement of all Pulaski County Special School District students with special emphasis on improving academic performance of African American and other at-risk students. Composed of eight all-day sessions during the academic year focused on relationship building, academic rigor, fun, and college graduation, goals of the Saturday Academy include developing better cognitive and noncognitive skills to succeed in college and facilitating college graduation by eliminating the need for developmental courses. Students completing the program and enrolling in one of the two partner colleges receive a $10,000 scholarship. Preliminary findings are impressive. [ABSTRACT FROM AUTHOR]

It has been suggested that we can tell whether two theories are equivalent by comparing the structure that they ascribe to the world. If two theories posit different structures, then they must be inequivalent. The aim of this article is to evaluate the extent to which this desideratum holds for the different standards of equivalence that are currently on the table. [ABSTRACT FROM AUTHOR]

Determining the strength of the ancient geomagnetic field is vital to our understanding of the core and geodynamo, but obtaining reliable measurements of the paleointensity is fraught with difficulties. Over a quarter of magnetic field strength estimates within the global paleointensity database from 0 to 5 Ma come from Hawaii. Two previous studies on the SOH1 drill core gave inconsistent, apparently method‐dependent paleointensity estimates, with an average difference of 30%. The paleointensity methods employed in the two studies differed both in demagnetization mechanism (thermal or microwave radiation) and Thellier‐style protocol (perpendicular and original Thellier protocols)—both variables that could cause the strong differences in the estimates obtained. Paleointensity experiments have therefore been conducted on 79 specimens using the previously untested combinations of thermal‐perpendicular and microwave‐original Thellier methods to analyze the effects of demagnetization mechanism and protocol in isolation. We find that, individually, neither demagnetization mechanism nor protocol entirely explains the differences in paleointensity estimates. Specifically, we found that non‐ideal multidomain‐like effects are enhanced using the original Thellier protocol (independent of demagnetization mechanism), often resulting in paleointensity overestimation. However, we also find evidence, supporting recent findings from the 1960 Kilauea lava flow, that microwave‐perpendicular experiments performed without partial thermal remanent magnetization checks can produce underestimates of the paleointensity due to unaccounted‐for sample alteration at higher microwave powers. Together, these findings support that the true paleointensities fall between the estimates previously published and emphasize the need for future studies (thermal or microwave) to use protocols with both partial thermal remanent magnetization checks and a means of detecting non‐ideal grain effects. Key Points: Causes for significant inconsistencies in important paleointensity records over the 0–45 ka time period in Hawaii are investigatedDisagreement is related to both the different demagnetization mechanisms and paleointensity protocols employedBoth previous records are likely biased with the true values expected to lie intermediate between them [ABSTRACT FROM AUTHOR]

Purcell-enhanced photon emission into a cavity is at the heart of many schemes for interfacing quantum states of light and matter. We show that the intra-cavity coupling of orthogonal polarisation modes in a birefringent cavity allows for the emitter and photon to be decoupled prior to emission from the cavity mode, enabling photon extraction efficiencies that exceed the, previously considered fundamental, limits of Purcell enhancement. Tailored cavity birefringence is seen to mitigate the tradeoff between stronger emitter-cavity coupling and efficient photon extraction, providing significant advantages over single-mode cavities. We then generalise this approach to show that engineered coupling between states of the emitter can equivalently 'hide' the emitter from the photon, ultimately allowing the extraction efficiency to approach its fundamental upper limit. The principles proposed in this work can be applied in multiple ways to any emitter-cavity system, paving the way to surpassing the traditional limitations with technologies that exist today. [ABSTRACT FROM AUTHOR]

Meeting the challenge of realizing fusion power production will require considerable and increasing investment in facilities for testing and development of fusion technology. Particularly important will be testing of components destined for the harsh in-vessel environment of the reactor. To help address this need, the U.K. Government is investing in major new fusion technology facilities, which will offer integrated laboratories covering the complete development life cycle from materials to manufacturing processes and load testing of components. A major part of these facilities shall be a test device named CHIMERA (combined heating and magnetic research apparatus), offering testing under fusion-relevant loads for meter-scale in-vessel component mock-ups. Among the major challenges addressed are electromagnetic loads, high heat flux (HHF), and proving complex and high-risk manufacturing. The ability to test technology in magnetic fields will be unparalleled and could prove vital for breeding blanket designs featuring a ferromagnetic structural material or a liquid metal breeder. The CHIMERA magnet system uses a split-pair NbTi superconducting magnet, combined with a vertical-axis pulsed resistive solenoid to simulate plasma disruptions. Furthermore, in order to provide semi-integrated testing including possible synergistic effects, CHIMERA will enable tests of resilience against magnetic and thermal loads in combination. The heating systems will deliver at least 0.5 MW/m2 at the module surface, HHF in localized areas, and power for volumetric heating of a module. This article introduces the CHIMERA device, reports the motivation and technical basis, describes the system specification, and outlines the future plan. [ABSTRACT FROM AUTHOR]

Psychoanalysis and public health appear to have an important but uneasy and rarely discussed relationship. Both fields have made significant contributions to mental health, despite major differences in their concepts and methods. Although controversies exist, we suggest that there are important areas of overlap and potential integration, with benefit to both fields and the understanding of human development and mental health. In order to explore these issues, we will first examine some of the early connections between psychoanalysis and public health. Next, we will focus on various assets and liabilities of each field. Third, we will look at one example of this integration, namely, physical punishment and violence. Finally, we will explore the question of resistance to social activism in the two fields. [ABSTRACT FROM AUTHOR]

In this article, I examine whether or not the Hamiltonian and Lagrangian formulations of classical mechanics are equivalent theories. I do so by applying a standard for equivalence that was recently introduced into philosophy of science by Halvorson ([ 2012 ], [ 2012 ]) and Weatherall ([ 2016a ]). This case study yields three general philosophical payoffs. The first concerns what a theory is, while the second and third concern how we should interpret what our physical theories say about the world. 1 Introduction 2 When Are Two Theories Equivalent? 3 Preliminaries on Classical Mechanics 3.1 Hamiltonian mechanics 3.2 Lagrangian mechanics 4 Are Hamiltonian and Lagrangian Mechanics Equivalent Theories? 4.1 Tangent bundle versus cotangent bundle 4.2 Tangent bundle versus symplectic manifold 4.3 Lagrangian vector field versus Hamiltonian vector field 5 Conclusion Appendix [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily characterized by the progressive impairment of motor functions. However, a significant portion of affected patients develops severe cognitive dysfunction, developing a widespread white (WM) and gray matter (GM) microstructural impairment. The objective of this study is to determine if Gaussian and non-Gaussian diffusion models gathered by ultra-high field diffusion MRI (UHFD-MRI) are an appropriate tool to detect early structural changes in brain white and gray matter in a preclinical model of ALS. ALS brains (G93A-SOD1mice) were scanned in a 16.7 T magnet. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) have shown presymptomatic decrease in axonal organization by Fractional Anisotropy (FA) and neurite content by Intracellular Volume Fraction (ICVF) across deep WM (corpus callosum) as well as superficial (cortex) and deep (hippocampus) GM. Additional diffusion kurtosis imaging (DKI) analysis demonstrated broader and earlier GM reductions in mean kurtosis (MK), possibly related to the decrease in neuronal complexity. Histological validation was obtained by an ALS fluorescent mice reporter (YFP, G93A-SOD1 mice). The combination of DTI, NODDI, and DKI models have proved to provide a more complete assessment of the early microstructural changes in the ALS brain, particularly in areas associated with high cognitive functions. This comprehensive approach should be considered as a valuable tool for the early detection of neuroimaging markers. [ABSTRACT FROM AUTHOR]

Developing an estate plan for a married couple when one spouse is not a U.S. citizen requires the consideration of both tax and nontax issues. The issues particular to noncitizen planning require a thorough analysis of the couple's assets and objectives even for planners generally familiar with the estate tax. This article will examine the rules surrounding the use of the marital deduction if the spouse is not a U.S. citizen. Additionally, it will discuss several estate and gift planning options that may address the clients' needs and provide planning flexibility. [ABSTRACT FROM AUTHOR]

Most conservation research aims to inform management of environmental challenges, but scientific evidence is used inconsistently in environmental programmes and practice. We used semi-structured retrospective interviews to ask 12 environmental scientists and 14 practitioners (land managers, park rangers, project managers and planners from natural resource management agencies) about factors that facilitated and hindered the use of scientific input during 15 environmental projects. We used the common factors from interviews to develop a process model describing how scientific input informs programmes and practice. The model emphasised the social dimensions of environmental projects which are often overlooked when these projects are planned, managed and evaluated. It highlighted the pivotal role of relationships in achieving outcomes which include creating practical, useful products and tools, and robust, credible and trusted evidence. By clarifying the process of how scientific knowledge informs environmental programmes and practice, the model enabled us to provide guidance about how to undertake transdisciplinary work and suggest indicators to track progress. Although derived from environmental projects, the guidance is likely to apply to other fields, particularly where different disciplines work together. [ABSTRACT FROM AUTHOR]

Virtual engineering is being widely adopted in diverse technical fields and has the potential to accelerate the realization of tokamak fusion energy. In this paper, we demonstrate, for the first time, the use of virtual engineering techniques to enhance the development cycle of a water-cooled divertor plasma facing component. The divertor concept under development is the thermal break, which aims to increase heat flux limits and DEMO-relevance by alleviating the high thermal mismatch stress between a tungsten monoblock and a copper alloy cooling pipe. Response surface-based design search and optimization is used to explore the potential of the concept and to inform the design of a high-heat-flux (HHF) mock-up. In developing a brazing manufacturing procedure, computed tomography scanning and subsequent image-based finite-element modeling revealed a defective joining process which would result in unacceptable divertor performance. The same techniques were used to develop an improved brazing procedure that was used to manufacture the mock-ups. A production defect was discovered by ultrasonic qualification testing, but a “virtual twin” model confirmed the acceptable performance of the mock-up under HHF. Indeed, all mock-ups were then subjected to at least 100 cycles of 20 MW/ $\text{m}^{2}$ HHF testing, with no signs of damage. The development of these virtual engineering and modeling techniques will facilitate criteria for design and component rejection, and in future enable predictive maintenance of components in service. Practical trials and experiments will remain essential to complement and validate simulations. [ABSTRACT FROM AUTHOR]

Mathematicians, physicists, and philosophers of physics often look to the symmetries of an object for insight into the structure and constitution of the object. My aim in this article is to explain why this practice is successful. In order to do so, I present a collection of results that are closely related to (and, in a sense, generalizations of) Beth’s and Svenonius’s theorems. [ABSTRACT FROM AUTHOR]

Wetheoretically and experimentally investigate nonlinear Zeeman (NLZ) effects within a polarised single-photon source that uses a single 87Rb atom strongly coupled to a high finesse optical cavity. The breakdown of the atomic hyperfine structure in the D2 transition manifold for intermediate strength magnetic fields is shown to result in asymmetric and, ultimately, inhibited operation of the polarised atom--photon interface. The coherence of the system is considered using Hong--Ou--Mandel interference of the emitted photons. This informs the next steps to be taken and the modelling of future implementations, based on feasible cavity designs operated in regimes minimising NLZ effects, is presented and shown to provide improved performance. [ABSTRACT FROM AUTHOR]

The purported fact that geometric theories formulated in terms of points and geometric theories formulated in terms of lines are 'equally correct' is often invoked in arguments for conceptual relativity, in particular by Putnam and Goodman. We discuss a few notions of equivalence between first-order theories, and we then demonstrate a precise sense in which this purported fact is true. We argue, however, that this fact does not undermine metaphysical realism. [ABSTRACT FROM AUTHOR]

Quine often argued for a simple, untyped system of logic rather than the typed systems that were championed by Russell and Carnap, among others. He claimed that nothing important would be lost by eliminating sorts, and the result would be additional simplicity and elegance. In support of this claim, Quine conjectured that every many-sorted theory is equivalent to a single-sorted theory. We make this conjecture precise, and prove that it is true, at least according to one reasonable notion of theoretical equivalence. Our clarification of Quine's conjecture, however, exposes the shortcomings of his argument against many-sorted logic. [ABSTRACT FROM AUTHOR]

Although medical students are taught clinical pharmacology using generic drug names, prescribing in hospitals often uses brand names. As a result, junior doctors may be prescribing drugs without knowing their nature or mode of action. We carried out a knowledge survey of 81 medical students and doctors at a 650-bed Australian teaching hospital to assess their knowledge of common drugs when given the brand name. We identified 20 commonly prescribed drugs and their brand names based on current hospital inpatients. No participant was able to provide the generic name, class or mode of action for all 20 drugs, with an average of 8.3 of 20 and 6.3 of the 10 most common drug names correctly identified. These data support calls to mandate prescribing using generic rather than brand names of drugs in hospitals. [ABSTRACT FROM AUTHOR]

Glymour (1970, 1977, 1980) and Quine (1975) propose two different formal criteria for theoretical equivalence. In this paper we examine the relationships between these criteria. [ABSTRACT FROM AUTHOR]

Objectives To characterize the safety of immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP). Methods Data were assessed from 9 phase 1 trials in healthy volunteers and recreational users of prescription opioids ( N = 405), including 5 single-dose and 3 multidose open-label pharmacokinetic studies of IR/ER OC/APAP and active comparators; and 1 randomized, controlled, single-dose human abuse potential (HAP) study comparing IR/ER OC/APAP, IR OC/APAP, and placebo in recreational users of opioids; and 2 phase 3 trials ( N = 701) including a 48-hour placebo-controlled safety and efficacy study in patients with moderate to severe postbunionectomy pain with a 14-day open-label safety extension and a long-term (≤ 35 days) open-label safety study in patients with chronic osteoarthritis pain or chronic low back pain. Results Adverse events (AEs) experienced by ≥ 10% of participants receiving IR/ER OC/APAP in all trials were pruritus, nausea, vomiting, dizziness, headache, and somnolence; these AEs occurred with similar frequency for equianalgesic doses of IR OC/APAP and IR OC but less frequently for IR tramadol HCl/APAP. In the HAP study, crushing IR/ER or IR OC/APAP tablets did not increase frequency of AEs. Constipation was experienced by < 10% of participants receiving IR/ER OC/APAP. No serious (SAE) or severe AEs were reported in phase 1 trials. In phase 3 trials of 8 reported SAEs, only 1 treatment-related SAE (hypersensitivity to placebo) required treatment discontinuation. No clinically meaningful changes in vital signs, oxygen saturation, electrocardiograms, or laboratory values were reported. Conclusions Safety and tolerability of IR/ER OC/APAP are similar to other low-dose opioid/APAP analgesics. [ABSTRACT FROM AUTHOR]

Logicians and philosophers of science have proposed various formal criteria for theoretical equivalence. In this paper, we examine two such proposals: definitional equivalence and categorical equivalence. In order to show precisely how these two well-known criteria are related to one another, we investigate an intermediate criterion called Morita equivalence. [ABSTRACT FROM AUTHOR]

Objective. To correlate abuse-related pharmacodynamic measures and pharmacokinetic measures after administering immediate-release/extendedrelease and immediate-release oxycodone/acetaminophen fixed-dose combination analgesics Design. Randomized, double-blind, active- and placebocontrolled, 7-way crossover study Setting. Contract research organization Subjects. Nondependent recreational users of prescription opioids. Methods. Participants received single doses of intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 15/ 650 mg, intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 30/1,300 mg, crushed immediate-release/extendedrelease and immediate-release oxycodone/acetaminophen 30/1,300 mg, and placebo. Measures of pharmacodynamics (pupillometry, drug liking, drug high, good drug effects) and pharmacokinetics were assessed predose and up to 24 hours postdose, and correlations between pharmacokinetic parameters and pharmacodynamic data were explored. Results. Of 61 participants, 55 completed all 7 treatments. Intact immediate-release/extended-release oxycodone/acetaminophen produced 50% lower oxycodone peak plasma concentration (Cmax) than immediate-release oxycodone/acetaminophen. Median oxycodone time to Cmax (tmax) was significantly longer (P<0.001) for intact immediate-release/ extended-release oxycodone/acetaminophen than immediate-release oxycodone/acetaminophen. The pharmacokinetics of crushed immediate-release/ extended-release and immediate-release oxycodone/ acetaminophen (30/1,300 mg) followed a similar pattern. Crushing did not shorten the median oxycodone tmax for immediate-release/extendedrelease oxycodone/acetaminophen (30/1,300 mg). Strong correlations were observed between oxycodone Cmax and area under the curve from time 0 to time x peak effects and area under the subjective effect curve from time 0 to time x for all subjective effects (R2=0.711-0.997). Conclusion. Immediate-release/extended-release oxycodone/acetaminophen produced lower oxycodone Cmax and longer tmax than immediate-release oxycodone/acetaminophen. Lower oxycodone concentrations, particularly at earlier time points, were strongly correlated with lesser positive subjective drug effects. [ABSTRACT FROM AUTHOR]

Context: Abuse potential of extended-release (ER) opioid tablets increases if tampering causes rapid opioid release. Objective: To evaluate the susceptibility to tampering of biphasic immediate-release (IR)/ER oxycodone (OC)/acetaminophen (APAP) tablets compared with IR OC/APAP tablets. Materials and methods: IR/ER OC/APAP and IR OC/APAP tablets were tested at room temperature and after heating, freezing and microwaving. Resistance to crushing was tested using manual and powered tools (e.g. spoons, mortar and pestle, blender, coffee grinder). Tampered tablets were tested for suitability for snorting, OC extraction in solvents and ease of drawing into a syringe. Dissolution of IR/ER OC/APAP in gastric fluid with and without ethanol was tested to determine the potential for facilitating precipitous release of opioid from the tablet. Results: IR/ER OC/APAP tablets were more crush resistant than IR OC/APAP tablets. Heating, freezing and microwaving had no effect on crush resistance of IR/ER OC/APAP tablets. Although a mortar and pestle pulverized IR/ER OC/APAP tablets, upon contact with solvent, the powder formed a thick gel judged unsuitable for absorption through the nasal mucosa and could not be drawn into a syringe. In contrast, powder from crushed IR OC/APAP tablets dissolved readily, was judged suitable for snorting, and was easily drawn into a syringe. Dissolution of IR/ER OC/APAP tablets in gastric fluid was slowed by the addition of ethanol. Discussion: IR/ER OC/APAP tablets are resistant to crushing and dissolution compared with IR OC/APAP tablets. Conclusion: IR/ER OC/APAP tablets may have less potential for abuse involving tampering compared with IR OC/APAP tablets. [ABSTRACT FROM PUBLISHER]

The standard view is that the Lagrangian and Hamiltonian formulations of classical mechanics are theoretically equivalent. Jill North ([2009]), however, argues that they are not. In particular, she argues that the state-space of Hamiltonian mechanics has less structure than the state-space of Lagrangianmechanics. I will isolate two arguments that North puts forward for this conclusion and argue that neither yet succeeds. [ABSTRACT FROM AUTHOR]

Aim: Alumina nanowell based disposable diagnostic biosensor for detecting and quantifying levels of prostate-specific antigen (PSA) from human serum has been designed, fabricated and tested. Materials & methods: The biosensors were designed by integrating nanoporous alumina membranes onto printed circuit board platforms, resulting in the generation of high-density nanowell arrays with gold base electrodes. The size and density of the nanowells were leveraged toward achieving sieving action for size-based exclusion of nonspecific molecules and size-based confinement of the target PSA molecules. Results & conclusion: We demonstrated PSA detection between 0.01 and 1000 ng/ml and detection and quantification of PSA from a 17 patient cohort validated using the Beckman Access system with >95% correlation. [ABSTRACT FROM AUTHOR]

Background. A fixed-dose combination biphasic immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB)/acetaminophen (APAP) tablet is being developed for the management of acute pain severe enough to require opioid treatment and for which alternative treatment options are inadequate.Methods. This Phase III, randomized, double-blind, placebo-controlled, parallel-group study evaluated the analgesic efficacy and safety of IR/ER HB/APAP (n= 201) versus placebo (n= 202) over a period of 48 hours in patients with acute moderate to severe pain following unilateral bunionectomy. Patients received three tablets of placebo or IR/ER HB/APAP as an initial dose (hour 0) followed by two tablets every 12 hours for a total daily dose of 37.5/1625 mg HB/APAP on day 1 and 30/1300 mg HB/APAP thereafter. The primary efficacy outcome was the summed pain intensity difference (SPID) over the first 48 hours (SPID48) after the first dose.Results. SPID48was significantly greater with IR/ER HB/APAP versus placebo (p< 0.001). SPID dosing interval analyses demonstrated consistent, superior pain relief with IR/ER HB/APAP for each dosing interval (allp< 0.001). Mean PID was greater with IR/ER HB/APAP versus placebo beginning 30 minutes after the first dose (p< 0.05), and IR/ER HB/APAP demonstrated faster median time to the onset of perceptible, meaningful, and confirmed pain relief (allp< 0.001). Mean total pain relief scores also indicated greater pain relief with IR/ER HB/APAP versus placebo throughout the 48-hour period (p= 0.012) for all comparisons. A greater proportion of IR/ER HB/APAP versus placebo patients was either “very satisfied” or “satisfied” with their pain relief (69.3% vs 49.4%;p< 0.001). Nausea was the most common treatment-emergent adverse event (TEAE; IR/ER HB/APAP, 25%; placebo, 7.9%). All TEAEs in IR/ER HB/APAP–treated patients were mild or moderate in severity.Conclusion. IR/ER HB/APAP provided rapid, significant, and consistent analgesic efficacy over a period of 48 hours in an established model of acute pain and was tolerated with a safety profile similar to other low-dose opioids. [ABSTRACT FROM AUTHOR]

Objective: To investigate the safety and satisfaction of patients treated ≤14 days after unilateral bunionectomy with extended-release oxycodone/acetaminophen (ER OC/APAP), a biphasic (ER and immediate release) fixed-dose combination analgesic being developed for moderate to severe acute pain. Research design and methods: This was an open-label extension (OLE) of a randomized, double-blind, placebo-controlled trial (DBRCT) of patients undergoing bunionectomy. Patients who consented to the OLE before entering the 48 hour DBRCT entered the OLE upon completing the DBRCT and during the OLE received two tablets of ER OC/APAP (15/650 mg total dose) every 12 hours for ≤14 days. ClinicalTrials identifier: NCT01484652. Main outcome measures: Treatment-emergent adverse events, physical examinations, vital sign measurements, and clinical laboratory testing were assessed throughout the study. Global assessments of treatment satisfaction were made at the end of the DBRCT and at each clinic visit during the OLE. Results: A total of 146 patients consented to the OLE before entering the DBRCT and 129 completed the OLE. Tolerability of ER OC/APAP during the OLE was consistent with that of an opioid product. Adverse events occurred during the OLE in 64 patients (43.8%); the most common were gastrointestinal events including nausea (17.8%), vomiting (7.5%), and constipation (6.2%). No changes in vital signs or clinical laboratory tests were considered by the investigator to be clinically significant. At all visits during the OLE, the majority of patients were satisfied or very satisfied with their medication. Limitations include a 14 day postprocedure study duration that may be confounded with natural healing time, and lack of a placebo arm. Conclusions: These results show that ER OC/APAP demonstrated an expected safety and tolerability profile and good patient satisfaction in a postsurgical model of acute pain. [ABSTRACT FROM AUTHOR]